tbuckley/cabot-search huggingface dataset:
CSIG-18. WNT SIGNALING MODULATES TUMORIGENIC FEATURES AND CELLULAR IDENTITY IN A MODEL OF LOW-GRADE GLIOMAGENESIS
Authors: Marilin Koch, Minh Deo, Michael Hoetker, Christel Herold-Mende, Wolfgang Wick, Sevin Turcan
Journal: Neuro-Oncology (2023)

Abstract RATIONALE: Isocitrate dehydrogenase (IDH)-1/2 mutations are known driver mutations for the development of low-grade gliomas (LGGs). However, secondary drivers are needed for tumor growth, and it remains unclear which co-factors and pathways are necessary to develop the LGG tumor phenotype. To identify additional players in IDH mutant-mediated oncogenesis, we investigated the effects of disrupting glioma-associated pathways in a tractable in vitro system of IDH-mutant malignant transformation. METHODS: A doxycycline-inducible IDHR132H expressing normal human astrocyte cell line was concomitantly treated with either a Wnt-activator/inhibitor (CHIR99021/IWP-2), TGF-β inhibitor (Repsox) or Notch inhibitor (YO-01027). IDH-associated CD171 marker expression changes were assessed with Flow cytometry, followed by transcriptional and proteomic analysis with RNA-Seq and mass spectrometry. Functional characterization entailed cell viability and clonogenic assays as well as cell cycle analyses. RESULTS: We observed significant IDH-related CD171 expression changes upon treatment with CHIR99021, Repsox and YO-01027. Wnt activation with CHIR99021 profoundly affected the IDH mutant-induced transcriptional landscape, leading to differential usage of LGG and stemness programs including altered expression of SOX4 and SOX11. On the protein level, Wnt activation additionally impacted pathways relevant for cellular architecture, specifically Rho-Rac-CDC42 signaling. This was also reflected by an altered cell morphology with small, rounded up cells, augmented clonal proliferation capacity and increased proportions of cell in S-phase. CONCLUSION: Wnt activation in a IDHR132H model system modulated LGG development, leading to differential expression of key LGG and stemness associated profiles, morphologic cell changes and increased replication capacity. While aberrant Wnt signaling is a common feature in glioblastoma, our data point to an effect also on low-grade gliomagenesis, therefore requiring further investigation.
NIMG-17. TOWARDS IMAGE - BASED PERSONALIZATION OF GLIOBLASTOMA THERAPY: A COMPREHENSIVE VALIDATION STUDY OF A NOVEL, DEEP LEARNING - DRIVEN TUMOR GROWTH MODEL FOR INDIVIDUALIZED RADIOTHERAPY
Authors: Marie-Christin Metz, Michael Griessmair, Ivan Ezhov, Jan Peeken, Jonas Weidner, Bjoern Menze, Benedikt Wiestler
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment planning. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy by estimating the tumor cell density in the whole brain. Here, we performed biological and clinical validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation. METHODS 124 patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration (Dw) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model that is adjusted to the patient’s anatomy using deep learning. To further evaluate clinical potential, we performed the same growth modeling on preoperative MRI data from 30 patients of our institution and compared model-derived tumor volumes (that serve as alternative clinical target volumes) and recurrence coverage with standard radiotherapy plans. RESULTS The parameter ratio Dw/ρ (p &amp;lt; 0.05 in TCGA) as well as the simulated tumor volume (0.5 tumor cell density) (p &amp;lt; 0.05 in TCGA/UCSF) were significantly inversely correlated with overall survival. We found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter ρ, proving its biological plausibility. Depending on the cutoff value for tumor cell density, we observed significant improvement of recurrence coverage without significantly increased total radiation volume utilizing model-derived target volumes instead of standard radiation plans. More precisely, a cutoff value of 0.5 tumor cell density yielded the best results here. CONCLUSIONS Identifying a significant correlation between computed growth parameters, and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve accuracy of radiation planning in the near future.
PATH-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A MULTI-CENTRIC, COLLABORATIVE STUDY LED BY THE IRRDC AND GLIOMA TASKFORCE
Authors: Logine Negm, Jiil Chung, Liana Figueiredo Nobre, Julie Bennett, Nicholas Fernandez, Martin Komosa, Cindy Zhang, Michelle Ku, Monique Johnson, Vanessa Bianchi, Melyssa Aronson, Lucie Stengs, Mary-Jane Lim-Fat, Julia Keith, Derek Tsang, Andrew Gao, David Munoz, Lananh Nguyen, Sunit Das, Adrian Levine, Anirban Das, Adam Resnick, Giles W Robinson, Kim Nichols, David A Wheeler, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary mismatch repair deficiency (pMMRD) is a pan-cancer mechanism caused by somatic mutations or inherited as part of Lynch Syndrome (LS) or constitutional mismatch repair deficiency (CMMRD). PMMRD results in universal hypermutation and microsatellite instability leading to chemoradiation resistance but sensitivity to immunotherapy. The prevalence of pMMRD in gliomas of children, adolescents, and young adults (CAYA), and the impact of germline inheritance is unknown. METHODS We harnessed functional genomic tools across population-based (Toronto), and multiple institutional (SJ, CBTN) cancer databases (n=1276) to determine the prevalence, subgroups, and impact of germline mutations in pMMRD gliomas. RESULTS Data from Toronto, SJ and CBTN reveals prevalence of 10%, 5% and 5% in pediatric high-grade gliomas (HGG). Molecularly, pMMRD is absent in gliomas harboring pediatric-type fusions, BRAF-V600E, and histone mutations, but enriched in HGG harboring IDH and TP53 mutations. In AYA (n=660), pMMRD was detected in 5% of IDH-WT and IDH-mutant high-grade astrocytomas, but notably absent in all oligodendrogliomas and other low-grade gliomas. Across this entire CAYA dataset, all except one pMMRD gliomas harbored germline MMR mutations (97%). Strikingly, LS predominated over CMMRD with significant difference in age of glioma onset (LS: 29-years versus CMMRD: 11-years; p&amp;lt; 0.001, IRRDC dataset). Survival analysis (Kaplan-Meier) confirmed the poor overall survival (OS) for pMMRD and other pediatric subtypes of HGG (3-year OS &amp;lt; 25%). In contrast, IDH-mutant pMMRD HGG have significantly worse OS than IDH-mutant non-pMMRD counterparts. Remarkably, immunotherapy significantly improves survival not only in children, but also for AYA patients with refractory pMMRD HGG (3-year OS &amp;gt; 50%). CONCLUSION This large study demonstrates that pMMRD drives a significant proportion of HGG across CAYA with an alarming impact of germline predisposition. Specifically, unrecognized AYA LS patients with MMRD HGG. These findings support universal screening for MMRD in HGG to identify patients for surveillance and immunotherapy.
TMIC-65. PP2A/STRN4 NEGATIVELY REGULATES STING-TYPE I IFN SIGNALING IN GLIOMA ASSOCIATED MACROPHAGES THROUGH YAP/TAZ
Authors: Winson Ho, Isha Mondal, Beisi Xu, Oishika Das, Rongze Olivia Lu
Journal: Neuro-Oncology (2023)

Abstract Glioma associated Macrophages/microglia (GAMs) are the predominant immune cells in the tumor microenvironment and drive immunosuppression. Strategies depleting GAMs have not demonstrated efficacy in clinical trials for GBM. It is critical to identify the underlying mechanisms how GAMs mediate immunosuppression. STING agonist, which activates the Type I IFN signaling in myeloid cells, is a promising strategy but also have shown limited efficacy in clinical trials. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in GAMs. Mice with macrophage PP2A deficiency exhibited improved glioma survival with radiation, which is known to activate STING. The glioma microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation in macrophages. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in glioma conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. We are also the first to demonstrate that in human GBM patients, YAP/TAZ signature was highly expressed in GAMs but not in non tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized glioma -conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4- YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in glioma-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize glioma to immunotherapy.
TMIC-66. SPATIALLY RESOLVED METABOLIC INTERACTIONS IN THE GBM MICROENVIRONMENT
Authors: Avirup Chakraborty, Diana Feier, Aryeh Silver, Changlin Yang, Dongtao Fu, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) contains cell populations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cancer stem cells (SCCs) preferentially engaging in lipid metabolism. The interaction between immune and tumor cells, and how tumor metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Our study allows for the molecular and spatial decoding of the heterogeneity within the GBM microenvironment, with a specific focus on unraveling the metabolic links that underlie the interplay between SCCs and the immune compartment. Our work indicates a new paradigm of communication in the TME of GBM, where SCCs play a pivotal role in shifting the tumor milieu toward an immunosuppressive phenotype, in part by recruiting specific tumor-promoting immune cells that stimulate SCC-driven tumor progression and provide metabolic support to these treatment-resistant cells. Our study delineates these metabolic communications and assesses the potential therapeutic effect of disrupting these interactions to treat GBM. The insights generated from this project uncover fundamental principles of the emerging connections between the tumor microenvironment, cell metabolism, anti-tumor immunity, and associated therapeutic vulnerabilities. In conclusion, our study provides a novel understanding of the role of metabolic interactions in the development of drug and immune resistant GBM. These findings suggest that targeting metabolic interactions, specifically between SCCs and tumor-associated immune suppressive cells, may be a promising therapeutic strategy for GBM.
PATH-33. MORPHOLOGY, MOLECULAR FEATURES, AND CLINICAL BEHAVIOR OF METHYLATION CLASS PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Chris Dampier, Niharika Shah, Kirstyn Galbraith, Sharika Rajan, Rachael Vaubel, Courtney Ketchum, Felipe D'Almeida Costa, Sima Ferman, Osorio Lopes Abath Neto, Nitin Wadhwani, Han Lee, Qinwen Mao, Lorraina Robinson, Michael Marshall, Tiffany Baker, Sahara Cathcart, Sanda Alexandrescu, Igor Fernandes, Jennifer Cotter, Ahmed Gilani, Matthew McCord, Diana Thomas, Jaiyeola Thomas-Ogunniyi, Peter Pytel, Beatriz Lopes, Kyle Conway, Jason Gregory, Felipe Andreiuolo, Jeffrey Nirschl, Zied Abdullaev, Martha Quezado, Caterina Giannini, Matija Snuderl, Kenneth Aldape
Journal: Neuro-Oncology (2023)

Abstract Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score &amp;gt;= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p&amp;lt; 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.
TMIC-18. CYTOMEGALOVIRUS ONCOMODULATION OF THE GLIOBLASTOMA TUMOR MICROENVIRONMENT: A ROLE FOR THE VIRAL-ENCODED GPCR, US28
Authors: Michael Kelly, Amanda Wass, Daniel Silver, Justin Lathia, Christine O'Connor
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a prevalent, malignant glioma, and patient prognosis is poor. Even with surgery and aggressive treatment, survival is a dismal 12-15 months. GBM therapeutic resistance is common, often resulting in tumor recurrence, due in part to cancer stem cells (CSCs) that are resistant to chemo- and radio-therapies. This highlights the need for novel treatments, which requires a deeper understanding of the GBM tumor environment. While controversial, emerging data implicate human cytomegalovirus (CMV) in GBM progression, including findings that CMV drives GBM cell proliferation. Our work confirms CMV accelerates GBM cell proliferation in vitro using patient-derived xenograft (PDX) GBM models. Intracranial injection of these infected cells into murine models also results in decreased survival relative to mock-infected cells, suggesting CMV infection influences survival in vivo. Further, we found the CMV-encoded G-protein coupled receptor (GPCR), US28, influences this, as infection of PDX-derived GBM cells in vitro with US28-deletion virus impacts cell proliferation. In murine models, we find wild type infected PDX-derived GBM cells result in a significant decrease in survival compared to mice receiving cells infected with CMV lacking US28, suggesting US28 expression confers improved overall survival in vivo. Additionally, we find expression of US28 is associated with significantly increased survival for female mice, whereas there was no statistical difference between male mice that received CMV-infected or uninfected GBM cells. This indicates CMV infection, and more specifically, US28 expression, adversely impacts survival of female mice. Collectively, our data further illuminate means by which CMV influences the GBM tumor microenvironment and survival. We are currently working to understand: 1) the impact of US28-mediated signaling pathways on the tumor microenvironment; and 2) the influence of US28 interacting partners on GBM progression, including EphA2, a receptor tyrosine kinase whose increased expression in GBM confers increased CSC invasiveness.
NIMG-63. GAMMA-BAND MODULATIONS OF ELECTROCORTICOGRAM (ECOG) INDUCED BY COGNITIVE-LINGUISTIC TASKS DURING AWAKE CRANIOTOMY FOR FEASIBLE FUNCTIONAL LANGUAGE MAPPING
Authors: Israt Tasnim, Priscella Asman, Chandra Prakash Swamy, Matthew Hall, Kyle Noll, Katherine Connelly, Sudhakar Tummala, Nuri Firat Ince, Sujit Prabhu
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Intraoperative functional language mapping has uncertainty in predicting language function and post-surgical outcomes. We study the feasibility of functional mapping using electrocorticogram (ECoG) gamma-band modulations induced by linguistic tasks having different complexity levels. METHODS Five subjects with left temporal lobe glioma underwent resection involving awake language mapping using a 4x8 ECoG electrode grid. A MATLAB/Simulink based real-time software system was used to map task-induced gamma-band modulations as 2D heat maps. Tasks included verbally responding to single word/tone categorization; object, action, written descriptive and auditory naming respectively. Auditory stimuli were provided during word/tone categorization (duration 300~500ms) and auditory naming tasks ( &amp;gt; 1s). Other tasks provided visual stimuli (line drawings or written phrases). Bipolar DCS (2~6 mA, 60Hz, 2s) was applied at different electrode pairs while repeating the naming tasks. RESULTS Cortical regions activated by word stimuli and the auditory naming task were similar; superior, middle temporal gyri (STG, MTG). Visual naming tasks modulated posterior MTG (pMTG) and STG (written naming). Reproducible speech arrests occurred during different naming tasks while stimulating specific electrode pairs, even though not all electrodes had strong task-specific activations. Considerable inter-personal variability of language areas identified with DCS was observed, despite the similarity of task-specific gamma-band modulated regions across subjects. Post-operative decline in language score was observed in one subject, with resection boundary covering gamma modulated regions during auditory processing tasks but no DCS identified region. CONCLUSION Intraoperative language mapping guided by gamma-band ECoG modulations induced by simple word/tone categorization task exhibited similar patterns to more complex naming tasks, suggesting this task may be a viable approach to localize functional cortex, especially in patients unable to reliably perform more difficult paradigms. Utilizing this method in conjunction with DCS mapping guided by visual naming tasks, eloquent cortical language areas may be better preserved reducing post-operative language deficits.
NIMG-59. RADIOMIC FEATURE CLUSTER ANALYSIS OF IDH-MUTANT GLIOMA SUBTYPES
Authors: Klara Willms, Saahil Chadha, Marc von Reppert, Divya Ramakrishnan, Jan Lost, Niklas Tillmanns, Leon Jekel, Sara Merkaj, Mariam Aboian
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION IDH-mutant glioma subtypes share similarities on MRI and histopathology but have distinct differences in survival based on their molecular subtypes. Radiomic features provide novel analysis of glioma imaging phenotypes that may not appear in clinical evaluations. We evaluated whether clustering of radiomic features of IDH-mutant gliomas could identify different subtypes based on the 2021 WHO classification. METHODS We extracted up to 5,763 radiomic features per case from pretreatment FLAIR and T1 post-contrast tumor segmentations of 206 patients with IDH-mutant gliomas WHO grade 2-4 using a standardized Pyradiomics 3.1.0 pipeline. Segmentations were performed using a semiautomatic workflow with a UNETR algorithm trained on the BRaTS 2021 dataset. To visualize high-dimensional feature space, we evaluated the following unsupervised clustering algorithms to differentiate tumor subtypes: PCA, t-SNE, UMAP, and PHATE. We performed redundancy reduction by calculating a Pearson correlation-matrix, and removed highly correlated features above a threshold of 0.7. Significant features were selected using the L1-norm regularization (LASSO). RESULTS The dataset of 206 patients included 19 grade 4, 28 grade 3, and 36 grade 2 astrocytomas as well as 23 grade 3 and 58 grade 2 oligodendrogliomas. The UNETR algorithm performed with a 0.85 Dice score on the segmentations. Clustering of the extracted 2D radiomic features from FLAIR and T1postgad using PCA, tSNE, UMAP, and PHATE did not identify distinct classes. To further analyze the two tumor entities, we applied XGBOOST, RandomForest, and KNN classifiers and found them to have AUCs &amp;lt; 0.5. CONCLUSIONS We showed that the spectrum of imaging features of IDH-mutant gliomas has a significant overlap on FLAIR and T1 post-contrast imaging. We propose that standard anatomical imaging does not provide sufficient information on these two sequences. To further identify specific subtypes of IDH-mutant gliomas, additional sequences, such as T2, ADC, SWI, and T1, can provide additional information.
PATH-66. SEQ-ING THE SINES OF CENTRAL NERVOUS SYSTEM TUMORS IN CEREBROSPINAL FLUID DNA
Authors: Christopher Douville, Chetan Bettegowda
Journal: Neuro-Oncology (2023)

Abstract It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We here introduce an analytic technique called Real-CSF to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) from throughout the genome are PCR-amplified with a single primer pair and the PCR products are evaluated by next generation sequencing. Real-CSF assesses genome wide copy number alterations in each of 39 chromosome arms as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancers and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard of care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.